Rising incidence of type 1 diabetes in Belgrade children aged 0-14 years in the period from 1982 to 2005.

BACKGROUND: Type 1 diabetes (T1DM) is an autoimmune disease in which both genetic and environmental factors play a role in the etiology. AIM: The aim of this study was to analyze the incidence of T1DM. METHODS: A retrospective technique was used to register all newly diagnosed cases of T1DM in Belgrade (Serbia) children at the age of 0- 14 yr between 1982 and 2005. The incidence was adjusted directly by age using the Segi's world population as the standard. A total of 702 cases was identified from the two sources: patients' records from two pediatric hospitals in Belgrade referent for the disease, and from the population based register. RESULTS: The average annual age adjusted incidence rate of T1DM for Belgrade was 10.4/100,000 [95% confidence interval (95% CI)=3.8-15.4]. It was slightly higher in boys than in girls. The age-specific annual incidence rates (per 100,000) for the age groups 0-4, 5-9, and 10-14 were 5.5 (95% CI=4.5-6.7), 11.9 (95% CI=10.5-13.5), and 15.4 (95% CI=13.8-17.1), respectively. Over the 24 yr incidence rates significantly increased by 8.5% for boys and 3.0% for girls. The highest increase of incidence rate was in the 5-9 age group. DISCUSSION: The results obtained are in line with data from other studies showing that the incidence of T1DM has been increasing in almost all populations worldwide.

Type 2 diabetes mellitus and impaired glucose regulation in overweight and obese children and adolescents living in Serbia.

An increase in the prevalence of pediatric type 2 diabetes mellitus (T2DM) has been reported by numerous studies in the United States during the past two decades. Available data from Europe are scarce, but also suggest the rising prevalence of this disease in overweight children. The aim of this study was to determine the prevalence of previously undiagnosed T2DM, impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) in a clinic cohort of otherwise healthy overweight and obese Caucasian children and adolescents living in Serbia. The study group consisted of 301 subjects (176 girls, 125 boys) aged 5.2-18.9 years, with body mass index >90th percentile. Oral glucose tolerance test was performed in all subjects. Previously undiagnosed T2DM was discovered in 0.3% (n=1) and impaired glucose regulation in 15.9% (n=48) of the subjects. Isolated IFG was detected in 4.3% (n=13), isolated IGT in 8.3% (n=25) and combined IFG and IGT in 3.3% (n=10) of the subjects. Disturbances of glucose metabolism were present in a substantial number of the subjects, which emphasizes the need for prevention and treatment of childhood obesity.

Several natural indicators of radial well ageing at the Belgrade groundwater source, part 1.

Over time, the radial collector wells of the Belgrade Groundwater Source, located in the alluvial sediments of the Sava River, exhibit a decline in discharge and a reduction in operating efficiency due to well ageing. An increase in hydraulic losses at the lateral screens, due to chemical and biochemical clogging, has been identified as the primary cause. Certain hydrogeological, hydrochemical and microbiological parameters reflect the well-ageing process and can, therefore, be considered as its indicators. An indicator-based determination of scale is an important aspect in the selection of appropriate well locations, structural characteristics, and maintenance approaches. Well ageing was studied over a period of 5 years (2005-2009). The objective was to investigate the causes of well ageing. The correlations established between the groundwater redox potential, the total iron concentration in groundwater, the grain-size distribution of the aquifer, and well discharge, are presented in the paper.

Molecular analysis of ring y chromosome in a 10-year-old boy with mixed gonadal dysgenesis and growth hormone deficiency.

Ring Y chromosome is a very rare chromosomal aberration. The published mixed gonadal dysgenesis (MGD) patients with a ring Y chromosome are short in stature, but are not growth hormone (GH) deficient. We present the molecular cytogenetic and molecular characterization of ring Y chromosome mosaicism in a 10-year-old boy with MGD whose short stature could be explained by the high percentage of cells monosomic for the X-chromosome, but also by the presence of severe GH deficiency. The ring Y chromosome in our patient is a de novo structural aberration. The father's karyotype was normal.

Granular cell tumor of the common hepatic duct presenting as cholangiocarcinoma and acute acalculous cholecystitis.

Granular cell tumors (GCT) are rare benign tumors. Less than 1% of GCTs involve the extrahepatic biliary tree. Most researches favour a Schwann cell origin. Patient, caucasion, female, 31-year-old presented with 4 month history of painless jaundice and pruritus. US and CT revealed dilatation of intrahepatic biliary tree and surgery was performed. Firm tumor mass was found above the conjunction of cystic duct and common hepatic duct (CHD) that caused obstruction and gallblader empyema. The patient underwent radical surgical procedure because Klatskin tumor was clinically suspected. Patohystology and immunohistochemistry confirmed granular cell tumor. Eight years after surgery the patient is wellbeing without symptoms. To our knowledge 69 cases of GCT of the extrahepatic biliary tree have been reported and none of the acute acalculous cholecystitis case acompanied by GCT of CHD. Granular cell tumors are rarely diagnosed preoperatively. Wide resection offers the best chance for cure.

[Causes of ambiguous external genitalia in neonates]. / Uzroci dvopolnog izgleda spoljasnjih genitalija kod novoredjencadi.

INTRODUCTION: The classification of disorders such as ambiguous genitalia in newborns is difficult because similar or identical phenotypes could have several different aetiologies. In most cases it was impossible to correlate the aetiology of the disorder and the appearance of the external genitalia [1-3]. A newborn with ambiguous genitalia needs prompt evaluation that will permit gender assignment and detection of life-threatening conditions (salt-losing crisis due to congenital adrenal hyperplasia or Wilms' tumour). We studied the causes and characteristics of ambiguous genitalia in newborn infants over the period from 1990 to 1999. PATIENTS AND METHODS: The following genital phenotypes are considered as ambiguous: 1. Hypospadias with no palpable gonads; 2. Hypospadias with micropenis and no palpable gonads or one palpable gonad; 3. Newborn with female external genitalia and a gonadal mass in labia or labial fusion and/or clitoral enlargement [1, 4]. The diagnostic evaluation of newborns with ambiguous genitalia consisted of history and physical examination, determination of serum electrolytes, plasma 17-hydroxyprogesterone (17-OHP), chromosome analysis on cultured lymphocytes, sonogram of the abdomen in connection with a genitogram; and whenever it was necessary, basal plasma concentrations of testosterone and, after the stimulation with human chorionic gonadotropin (hCG), laparotomy for definitive determination of gonadal histology. All disorders with ambiguous genitalia have been classified in four groups: [6]: 1. Female pseudohermaphroditism (FPH); 2. Male pseudoherma phroditism (MPH); 3. True hermaphroditism (TH); 4. Asymmetrical gonadal dysgenesis (ASGD). RESULTS: The causes of sexual differentiation disorders in a group of 38 newborns with ambiguous genitalia are presented in Table 1. Main criteria for the diagnosis of FPH were normal female karyotype 46, XX, masculinization of external genitalia and no palpable gonads. Genitography revealed urogenital sinus and vagina, and ultrasound examination the uterus. During initial examination seven of 15 newborns with congenital adrenal hyperplasia (CAH) (Table 2) due to 21-hydroxylase (P450c21) deficiency (21-OHD) had clinical or laboratory signs of adrenal crisis. Two children had a simple virilizing form of 21-OHD. The female gender was chosen for these children. In other three patients with FPH isolated clitoral hyperplasia or labial fusion was the main reason for the studies. The common characteristics of newborns with MPH were as follows: normal male karyotype 46,XY with normally developed or dysgenetic testes, and/or good response to hCG stimulation. The complete androgen insensitivity (testicular feminization) was detected in two children (Table 3) with female external genitalia and palpable gonads in the labial folds, and female gender was chosen. The Denys-Drash syndrome was detected in one newborn with ambiguous genitalia, no palpable gonads, and normal response to hCG, and ultrasound findings of multiple bilateral renal tumours were identified as Wilms' tumour. In other newborns with MPH incomplete masculinization consisted of hypospadias, mostly of perineoscrotal type and of micropenis (penile size less than 2 cm) and/or bilateral or unilateral cryptorchidism (Table 3). In all children male sex was chosen. Asymmetrical gonadal dysgenesis was detected in two newborn infants. Both children had 46,XY/46,XX karyotype, testes on one side of the abdomen, and streak gonad on the other, developed vagina, uterus and unilateral Fallopian tube, and were raised as females. True hermaphroditism was established in one newborn with 46,XX karyotype, with a testis on one side of the abdomen and an ovotestis on the other side. The parents decided for male gender. The aetiology of ambiguous genitalia was not established in five children; in two children with 46,XY and one with 46,XX karyotype (with palpable gonads) the diagnostic study was not completed. CONCLUSIONS: The most common cause of ambiguous genitalia in our newborn patients was CAH due to 21-OH deficiency [2, 4, 6, 7]; 87 percent of patients had salt wasting form of the disease. In the majority of patients the appearance of the external genitalia made possible the detection of the disease immediately after the birth. So, the relative high incidence of adrenal crisis in our patients with CAH (38%) seems unreasonable. The decision for gender assignment was possible after the appropriate study of the nature of the disorder. The causes of MPH are numerous and heterogeneous [1, 3, 8]. With the exception of two patients with complete form of androgen insensitivity, in all newborns with MPH the male gender predominated. The appearance of external genitalia with severe perineoscrotal hypospadia and/or micropenis suggested the possibility of incomplete androgen resistance. If a male assignment is being considered, the response of the phallic size to treatment with testosterone was recommended. If penile size did not reach the 2.5 cm range or above, a male sex assignment was not advisable [1]. It is important for the paediatric surgeon to be involved in the diagnostic evaluation of these infants to plan the timing and techniques of the surgical reconstruction [6]. The decision to raise a patient with sex chromosome mosaicism, true hermaphroditism, or mixed gonadal dysgenesis as either a male or a female was based on the appearance of the external genitalia and possible fertility [1, 9]. The parental decision of male sex in our patients with true hermaphroditism could not be considered as optimal.

Transient neonatal diabetes mellitus in a child with paternal uniparental disomy of chromosome 6.

We report a male infant with transient neonatal diabetes mellitus (TNDM; MIM 601410), macroglossia, hypertelorism, umbilical hernia, inguinoscrotal hernia and onychomycosis. Diabetes mellitus was diagnosed 10 days after birth and resolved after 6.5 months of treatment. Genetic investigation indicated the presence of paternal uniparental disomy of chromosome 6 (UPD 6). The finding of paternal UPD 6 allows prediction of a transient, rather than permanent NDM, and no increased recurrence risk of TNDM in subsequent pregnancies. Therefore, finding of NDM should be a strong indicator for genetic testing.

[Schimke immuno-osseous dysplasia]. / Simkeova imunsko-kostana displazija.

Schimke immuno-osseous dysplasia (OMIM *242900) is a rare autosomal recessive disorder that affects primarily the bone, the immune system, the kidneys, the skin and the vascular system. The patients have intrauterine growth retardation, short stature with short neck and trunk, peculiar clinical phenotype: triangular face, broad nasal bridge, bulbous nasal tip, small palpebral fissures, long upper lip and low hairline. The characteristic features include spondyloepiphyseal dysplasia, hyperpigmented maculae, proteinuria with progressive renal failure, lymphopenia with recurrent infections and cerebral ischaemia. We describe a girl, 5 years old, with short-trunk type of dwarfism (height 75 cm, below 3rd centile), short neck, accentuated lumbal lordosis and protruding abdomen. The patient had peculiar face with a broad, depressed nasal bridge, bulbous nasal tip, and slightly elongated upper lip. The hair was thin and sparse. Numerous pigmented spots resembling lentigines were visible on the trunk and abdomen. Radiographs showed spondyloepiphyseal dysplasia. At the age of 2 years laboratory analyses showed normal growth hormone secretion, normal thyroid function tests, normal female karyotype and no mucopolisachariduria. Since the age of 4 years, several episodes of transitory right-sided hemiparesis with spontaneous recovery, were observed. Seizures occurred at 5 years of age, when the MRI brain imaging showed multiple areas of ischaemia. She also experienced transient nephrotic syndrome, lymphopenia and low IgG accompanied by septicaemia.

[Ectopy of the thyroid gland as cause of neck or tongue base tumour]. / Ektopija tireoidne zlezde kao uzrok tumora na vratu ili na bazi jezika.

One of the most important causes of congenital hypothyroidism found in 35-42% of cases, is ectopy of the thyroid gland. Thyroid gland can be displaced at base or under the tongue, or under the hyoid bone. Ectopic gland is also hypoplastic, secreting not enough amounts of thyroid hormones. By negative feedback mechanism that cause elevation of TSH. Under the permanent TSH stimulation ectopic gland can enlarge appearing as a neck or tongue base "tumour". In this way, by measuring TSH level in a newborn, all children with thyroid gland ectopy can be detected. Ectopy of the thyroid gland as cause of congenital hypothyroidism was present in three patients as a tumour of neck or tongue base. After surgical removal of the "tumour", histopathologic analysis revealed that it was the thyroid tissue. No patient passed the thyroid function test nor identification of the thyroid tissue (ultrasound or scintigraphy) before surgery. All were born in the regions of Serbia where screening for congenital hypothyroidism was not carried out at all or only temporary. Screening of newborns for congenital hypothyroidism is based on measuring TSH level. By this method all patients with thyroid gland ectopy can be detected. Scintigraphic examination after surgery detected no thyroid tissue and replacement therapy with Na L-thyroxine started.

MRI evaluation of the knee in rheumatoid arthritis.

The knees of forty-three patients suffering from rheumatoid arthritis (RA) were examined using pre- and post-contrast MRI in an attempt to assess the extent and frequency of all abnormalities in the RA knee. Features evaluated by MRI were: synovial thickening, joint effusion, bone destruction, popliteal cysts, periarticular soft tissue swelling, abnormal tendons and bone marrow changes. A scoring system (0-2) was used to determine the relationship between the various signs of RA in order to identify those that may be relevant for the assessment of therapeutic response. It seems that the assessment of inflamed synovium is the major criterion for the determination of disease activity in RA.

[Relationship between height velocity and growth hormone secretion in normal and short prepubertal children]. / Brzina rastenja i sekrecija hormona rasta kod dece niskog i normalnog rasta u prepubertetskom uzrasty.

In 60 prepubertal children of both sexes, aged between 6.4 and 15.5 years, with normal or short stature and growing with heigh velocity standard aviation scores (SDS) between 2.69 and -5.75, we has performed 12h noctunral growh hormone (GH) profiles. We found a statistically significant relationship between growth velocity and growth hormone secreation in the group of 60 children with different degrees of GH deficiency, short normal children and children with normal stature. The relationship was expressed with a logarithmic type of curve. In the gruop of 13 children with constituonal growth delay or in the group of 9 children with the familial short stature, we did not find a significant relationship between growth velocity and GH secretion. In the group of short children with complete GH deficiency there were marked individual differences in growth velocity after the beginning of thyroid replacement therapy; children with secondary hypothyroidsm were growing significantly faster than children with normal thyreotrpic function. In our opinion the height velocity is controlled with thyroid hormones, genetic influences, and possibly, with other unknown factors which operate independntly of GH secreation during prepubertal years.

[Growth hormone response to insulin-induced hypoglycaemia in children with normal stature or normal variant short stature]. / Nivoi hormona rasta u serumu u toku standarnog insulinskog testa kod zdrave dece normalnog i niskog rasta.

Definition of normal values of growth hormone (GH) during insulin-induced hypoglycaemia was based on experience in a group of 30 pre-pubertal children (age range 6.4-16.8 years) with normal stature or with normal variant short stature. The growth velocity was calculated in all children. The maximal GH values to insulin-induced hypoglycaemia and the mean GH levels of a 12 hours nocturnal period (sampled at 30-min intervals from 8 p.m. to 8 a.m. hours) were also determinated. In a group of 13 children with normal or short stature and normal growth velocity it was established that the GH response in blood higher than 20 mlU/l (10 ng/ml) represents lower limit of normal range and excludes the possibility of GH deficiency. Comparisons of the maximal values of GH to insulin-induced hypoglycaemia and mean GH levels during twelve-hour nocturnal period in a group of seventeen short normal children suggested that GH responses to insulin-induced hypoglycaemia between 15 - 20 mlU/l also most frequently represent normal endogenous secretion of GH.

Focal glomerular sclerosis and nephrotic syndrome in spondyloepiphyseal dysplasia.

The association of a spondyloepiphyseal dysplasia and disproportionate short stature with focal glomerular sclerosis is reported in two girls. Renal disease manifested by proteinuria at the age of 2.5 and 11 years, leading to treatment-resistant nephrotic syndrome over 15 and 45 months, respectively. One patient went into end-stage renal failure shortly after nephrotic syndrome developed, the other died from sepsis. The association of spondyloepiphyseal dysplasia and focal glomerular sclerosis with nephrotic syndrome may represent a distinct disease entity.

Magnetic resonance imaging of bone destruction in rheumatoid arthritis: comparison with radiography.

Bony changes in forty-four knees of patients with clinically established rheumatoid arthritis (RA) were examined using magnetic resonance imaging (MRI) and plain film radiography. In all cases MRI was clearly superior to radiographs, demonstrating 25 marginal erosions and 42 subchondral cysts, while the number seen on radiographs was 3 and 8, respectively. These results emphasize the problems in visualizing bone erosions in large joints using plain films. MRI is the method of choice for detecting early changes in RA, not only because of its high sensitivity, but also because of the ability of contrast-enhanced MRI to provide physiological characterization of these lesions.

[Delayed effect of cyclophosphamide on testicular function after treatment of nephrotic syndrome in childhood]. / Udaljeni efekti ciklofosfamida na funkciju testisa posle lecenje nefrotskog sindroma u detinjstvu.

The authors present the results of study of testicular spermatogenetic and endocrine function in adult males treated with high doses of cyclophosphamide for nephrotic syndrome during childhood and/or adolescence. Seventeen males, mean age of 22.5 years (range, 17-30) were examined after mean follow-up of 11.8 (5-17.3) years. Mean age at the time of treatment was 10.8 (3.6-17.6) years; mean duration of cyclophosphamide treatment was 240 (39-701) days, and mean total cumulative doses were 641 mg/kg body weight (103-1999) or 16.4 (3.9-55.7) grams. All the patients undergone normal pubertal development and had normal sexual characteristics. Eleven were normospermic (more than 20 x 10(6)/ml spermatozoa), one oligospermic and five azoospermic. There was a significant inverse correlations of sperm density with cyclophosphamide dosage and duration of treatment. These variables seem to be more important for cyclophosphamide toxicity, than stage of sexual development at time of treatment. Raised basal and stimulated FSH concentrations in oligoazoospermic patients were in keeping with impaired spermatogenesis. These patients had also raised basal and stimulated LH concentrations suggesting compensated Leydig cell failure. Subgroup of normospermic patients with lower spermatozoa concentrations (20-40 x 10(6)/ml) had significantly raised FSH and LH responses on stimulation with gonadotropin releasing hormone, suggesting dysfunction both tubular and interstitial cell component of the testis. In other normospermic patients gonadotropin responses were not different from controls. Basal and HCG stimulated testosterone concentrations showed no differences between patients and controls. These results confirmed significant inverse correlations of cyclophosphamide dosage with its effect on spermatogenesis, and documented the long-term effect on the Leydig cell function requiring further follow-up.

[Clinical and laboratory characteristics of chronic autoimmune thyroiditis in children and adolescents]. / Klinicke i laboratorijske karakteristike hronicnog autoimunog tireoiditisa u dece i adolescenata,.

Clinical and laboratory characteristics of chronic autoimune thyroiditis were analysed in sixty-seven patients (55 girls). At the time of diagnosis the mean +/- SEM age of 67 patients was 11.6 +/- 2.9 years. Diagnosis of the disease was based on the findings of the enlarged thyroid gland on palpation and positive thyroglobulin and/or microsomal antibodies. The assessment of thyroid function was based on clinical diagnosis and on the levels of thyroid-stimulating hormone and thyroxine. Initially 36 (53.7%) of 67 patients were euthyroid, 15 (22.4%) were hyperthyroid and 16 (23.9%) were hypothyroid. In addition to the well known clinical signs of chronic autoimmune thyroiditis, the palpable lymh nodes in the immediate proximity of the thyroid gland were found in high frequency (47%) in our patients with euthyroid or hyperthyroid goiter. The thyroid function was followed-up in fifty-three patients for an average of 2.6 (0,3-7) years. No progression to hypothyroidism was clinically observed, or demonstrated by laboratory findings in euthyroid patients. In seven patients with subclinical hypothyroidism at the time of diagnosis spontaneous recoveries of thyroid function occurred. The majority of hyperthyroid patients (80%) required a prolonged antithyroid treatment. In all patients with clinical and laboratory signs of hypothyroidism the replacement therapy with thyroxine was started at the time of diagnosis.

[Short stature as major clinical sign of coeliac disease in children]. / Niski rast kao osnovni klinicki znak celijakije kod dece.

Coeliac disease was found in 16 patients. 3-15 years of age, examined for short stature of unknown origin. Frequency of some clinical and laboratory findings was analysed. The anamnestical data on diarrhoea and/or abundant stools feces before and during treatment were found in 11 patients (68.7%) abdominal pains in 4 subjects (25%) and anaemia resistent to iron in 5 individuals (31.2%). The clinical examination revealed, in addition to low height, a large abdomen in 11 cases (68.7%), pale skin in 10 patients (62.7%) and loss of subcutaneous fat tissue in 7 subjects (43.8%). Retardation of osseous maturation of more than 25% of chronologic age was found in 14 children (87.5%). The low erythrocyte and haemoglobin concentrations were found in 68.7% of cases, and iron in the serum in 63.3% of children. The pathologic D-xylose test was found in 7 children. The insufficient response of the growth hormone in the serum during insulin testing had its maximal value below 15 mlJ/l in 6 of 15 children (37.5%). On the basis of these results it can be concluded that in children with short stature the finding of one or several of the above mentioned symptoms and signs, or laboratory disturbances, should be taken into account regarding coeliac disease. However, in these patients the partial lack of the growth hormone should also be taken into account.